Vulnerabilities in osteosarcoma and breast cancer

骨肉瘤（OS）是儿科患者癌症相关死亡的主要原因。 在过去的三十年里，这种癌症的死亡率没有实质性变化， 部分原因是缺乏FDA批准的靶向治疗。了解OS的病因 是开发新的治疗方案的迫切需要。基因组测序研究没有 找到任何主要的可行动目标我们的策略是识别OS细胞的生存信号 与p53通路有关。除了人OS细胞系，我们一直在使用间充质干细胞。 干细胞（MSC）作为模型，因为它们是OS细胞的假定起源细胞。期间 在本报告所述期间，我们取得了若干重大进展。首先，我们发现p53 抑制MSC中RUNX 2的表达，p53缺失使这些细胞倾向于成骨细胞 分化，提供了一个解释的临床观察，OS是紧密 与p53缺失有关。其次，我们将CBFB/RUNX 2轴确定为OS中的存活信号， 细胞第三，我们发现，在p53缺失的背景下，癌基因决定了肿瘤的类型。 来源于MSC的肉瘤。例如，cFos-Sox 9轴促进成软骨细胞OS 从p53 null MSC。未来的研究重点是进一步研究促生存 我们希望我们会发现操作系统在RUNX 2监管方面的漏洞 基因表达，可用于开发一种新的治疗OS。我们最近 我们加大了研究乳腺癌翻译失调的力度， 发现CBFB在乳腺癌的翻译调节中的新功能。的 CBFB基因在大约5%的乳腺肿瘤中发生突变;然而，它在乳腺癌中的功能， 癌症是未知的。我们是第一个报道CBFB具有肿瘤抑制作用的人 在乳腺癌中。其潜在的分子机制完全出乎意料。相比 CBFB是一种转录因子，我们发现细胞质CBFB 直接调节乳腺癌细胞中的翻译。因为转录事件是 翻译是基因表达中的一个重要步骤， 癌症脆弱性事实上，我们的初步研究表明，下游事件 引起的CBFB介导的翻译失调，可以进一步利用，以确定 乳腺癌的脆弱性。因此，理解CBFB调控的翻译， 乳腺癌已经成为我研究计划的一个主要焦点。正在进行的努力是 专注于研究代谢转变和自噬失调引起的 乳腺细胞CBFB缺陷。

Osteosarcoma (OS) is a leading cause of cancer-related death in pediatric patients. Mortality rates for this cancer have not changed substantially during the last three decades, partly due to the lack of an FDA-approved targeted therapy. Understanding the etiology of OS is a critical need for developing new treatment options. Genomic sequencing studies did not find any dominant actionable targets. Our strategy is to identify OS cells' survival signals related to the p53 pathway. In addition to human OS cell lines, we have been using mesenchymal stem cells (MSCs) as a model since they are the putative cell-of-origin of OS cells. During this review period, we have made several critical advances. First, we showed that p53 represses RUNX2 expression in MSCs, and p53 loss predisposes these cells to osteoblast differentiation, providing an explanation for the clinical observation that OS is tightly associated with p53 loss. Second, we identified the CBFB/RUNX2 axis as a survival signal in OS cells. Third, we uncovered that in the context of p53 loss, oncogenes determine the types of sarcomas originating from MSCs. For example, the cFos-Sox9 axis promotes chondroblastic OS from p53 null MSCs. Future studies are focused on further investigating the pro-survival function of RUNX2 in OS. We hope that we will find vulnerabilities of OS in RUNX2-regulation gene expression that can be exploited for developing a novel treatment of OS. We have recently ramped up our efforts to study translation dysregulation in breast cancer based on our discovery of a new function for CBFB in the translational regulation of breast cancer. The CBFB gene is mutated in about 5 percent of breast tumors; however, its function in breast cancer had not been known. We were the first to report that CBFB has a tumor-suppressive role in breast cancer. The underlying molecular mechanism was completely unexpected. In contrast to the well-accepted view that CBFB is a transcription factor, we found that cytoplasmic CBFB directly regulates translation in breast cancer cells. Because transcriptional events are difficult to target, translation represents a vital step in gene expression for identifying cancer vulnerabilities. Indeed, our preliminary studies suggested that downstream events caused by deregulation of CBFB-mediated translation could be further exploited to identify vulnerabilities in breast cancer. Therefore, understanding CBFB-regulated translation in breast cancer has become a major focus of my research program. Ongoing efforts are concentrated on investigating the metabolic shift and autophagy dysregulation caused by the CBFB defect in breast cells.